Drug abuse affects millions of people worldwide and begins against a backdrop of vulnerability based upon genetic, environmental, and psychological factors. Investigations into psychological characteristics associated with drug abuse have revealed impulsivity as a major risk factor for initiation, maintenance, and relapse to drugs of abuse such as cocaine. Thus, understanding the neurobiological substrates of impulsivity is critical for developing prevention and treatment strategies. Despite significant advances in understanding the general neurobiology of impulsivity, there is a fundamental gap in our knowledge of the factors that determine how individual differences in impulsivity that may confer addiction vulnerability. Using animal models of impulsive action and cocaine-seeking, the objective of this proposal is to identify neurobiological differences between inherently high and low impulsive (HI and LI) outbred rats and relate those differences to the susceptibility to cocaine-seeking behavior. The neural systems supporting impulsive action include limbic system regulators of reward and motivation as well as cortical structures that exert inhibitory control, such as the prefrontal cortex (PFC). Inhibitory control from the PFC is heavily modified by dense serotonin (5-HT) innervation, and the 5- HT2A receptor (5-HT2AR) has been shown to play an important role within the PFC in both impulsive action and reactivity to cocaine-associated cues. Our preliminary data strongly suggest that 5-HT2AR functional regulation contributes to individual differences in inherent impulsivity. We hypothesize that hyperfunctional 5-HT2AR tone in the PFC underlies a predisposition to high impulsive action and cocaine-seeking behavior. Specific objectives include: (1) determine differences in 5-HT2AR availability and expression between HI and LI rats using biochemical and pharmacological methods; (2) identify pharmacological sensitivity of HI vs. LI rats to the effects of a 5-HT2AR agonist and antagonist; (3) assess the effects of synthetic depletion of PFC 5-HT2AR expression on impulsivity and cocaine-seeking behavior. Completion of these objectives will provide the applicant with training in new concepts and methodologies, including the neurobiology of impulsivity and addiction, the design and interpretation of behavioral and neurochemical experiments, principles and methods of neuropharmacology, and the neuroscientific application of genetic technology. The experiments proposed within these objectives are expected to provide novel insights into the role of the 5-HT2AR as a driver of inherent impulsivity and as a mechanistic integrator of impulsive action and cocaine-seeking behavior. This proposal will advance our current knowledge of 5-HT2AR function in impulsivity toward a new understanding of why some individuals are more impulsive than others. This contribution is significant because the outcomes will inform efforts to develop therapeutic intervention for the management of impulse control in addictive disorders as well as other psychiatric disorders in which impulsivity is a contributing feature. PUBLIC HEALTH RELEVANCE: Drug addiction is a highly prevalent and costly disorder associated with deficits in impulse control. Our goal is to advance our understanding of neurobiological factors that contribute to the vulnerability to impulsive behavior and susceptibiliy to drug relapse, focusing on the role of the 5-HT2AR as a mechanistic integrator of impulsive action and cocaine-seeking behavior. This contribution will inform efforts to develop therapeutic interventions to manage impulse control in addictive disorders in order to reduce occurrence of relapse and promote abstinence.